The present invention relates to pharmaceutical compositions in liquid form which are suitable for the delivery of active ingredients using various routes of administration, in particular injection or topical administration into the nose, an ear, or an eye of a patient.
Pharmaceutical compositions in liquid form represent one of the preferred types of drug formulations. In the context of oral pharmacotherapy, liquid formulations are important for patients who have difficulties swallowing tablets, capsules or other solid dosage forms, such as children or elderly patients, or when substantial dosing flexibility is required. Certain topical routes of administration, such as nasal, otic, or ophthalmic administration, typically require the liquid form in order to provide for an efficient delivery of the active ingredient and a patient-friendly mode of use. Moreover, injectable drug products are mostly in liquid form as the injection or infusion of liquids is particularly convenient and flexible compared to other parenteral dosage forms.
The most simple type of liquid formulation is a solution, such as an aqueous solution of the active pharmaceutical ingredient. In certain cases, however, the development of a more complex formulation such as a suspension may be considered. For example, if a drug substance is very poorly soluble in aqueous or other biocompatible solvent systems, or if it is hydrolytically labile, a simple solution may not be feasible or represent the best choice. Another occasional motivation to formulate a drug suspension is in order to achieve a prolonged pharmacological effect by slow dissolution and uptake of the active ingredient.
Examples of pharmaceutical suspensions for nasal use include Avamys® (active ingredient: fluticasone furoate), Nasonex® (active ingredient: mometasone furoate), and Pulmicort® Topinasal (active ingredient: budesonide). An ophthalmic suspension that has reached the market stage is, for example, Livocab (active ingredient: levocabastine). Among the commercial suspension formulations for injection are Humalog® (active ingredient: insulin lispro), Tardocillin® for injection (active ingredient: benzathine benzylpenicillin), as well as most vaccines.
Common problems associated with pharmaceutical suspensions are usually related to physical stability issues, potential irritability, and/or manufacturing challenges. Obviously, suspensions are prone to physical changes of various types, all of which may have impact on drug product quality and performance.
For example, suspended particles may flotate or sediment, depending on their density relative to that of the liquid phase in which they are dispersed. Along with flotation or sedimentation, the suspended particles may aggregate, and depending on the forces by which the particles attract each other, the aggregates thus formed may be rather difficult to resuspend. A further problem is that in suspensions having non-uniform particle sizes there is a tendency for smaller particles to gradually dissolve, whereas larger particles grow through the deposition of dissolved material onto their surfaces (Ostwald ripening). In result, the particle size distribution of a suspension may become broader over time. Particles which grow beyond a certain size may be unsuitable for the intended use; for example, they may occlude an injection cannula or, in case of ophthalmic administration, irritate or even damage the ocular surface.
In general, suspensions of particles have a somewhat higher risk of irritating or damaging certain issues simply by their physical presence. This is true for parenteral injection where suspended particles would bring about the risk of embolic events in the vasculature in case of injection into the bloodstream, for which reason suspensions for intravenous use are normally discouraged, unless it can be assured that all particles are in the low micron or submicron size range and thus not embolic. But also for intradermal, subcutaneous or intramuscular injection it has been found that suspended particles above a certain particle size may lead to some—typically mild—irritation at the injection site, especially of the injected amount of material is relatively large.
Neither is it straightforward to manufacture a pharmaceutical suspension in a highly reproducible manner as is required in particular for non-oral products. If the particle size and the distribution thereof is critical, which is likely in the case of a parenteral suspension, but to some degree also for an ophthalmic suspension, significant process engineering efforts may be required in order to ensure the reproducibility of the physical properties of the formulation. Moreover, if the product is required to be sterile, which is always the case for an injectable or ophthalmic product, heat sterilisation will normally be extremely difficult in view of the major physical changes which the product undergoes during heating, and sterile filtration which is typically performed with products that cannot be heat sterilised will be generally unfeasible. The remaining options include aseptic processing, which is technically complex and challenging, and gamma sterilisation, which may be feasible depending on the chemical stability of the drug substance and of the excipients.
Drug products for the treatment of ophthalmic diseases or conditions are mostly formulated as liquid compositions for local administration. Four ophthalmic target sites for drugs may be differentiated: (a) the conjunctiva, the eye lids, and other structures of the front of the eye; (b) the cornea; (c) the anterior and posterior chamber and their associated structures; and (d) the vitreous cavity (NM Davies, Clin. Exper. Pharmacol. Physiol. 27, 558-562, 2000). Except for the vitreous cavity or body, these targets may be reasonably reached by many therapeutic compounds when administered as eye drops or ointments. In contrast, if the vitreous body is the target, it may be difficult to obtain therapeutic drug concentrations after local topical administration, and systemic or intravitreal administration are typically preferred. For the other targets, the benefits of non-invasive local administration are similar to other topical routes, in particular in that it provides an opportunity to achieve therapeutic drug concentrations at the site of action while minimising the amount of drug in the systemic circulation.
At the same time, achieving local bioavailability of a drug at an ophthalmic target site after topical administration is complicated by several anatomical and physiological factors. A requirement for effective delivery is that a drug formulation introduced to the pre-ocular area must be retained at this site for a sufficient time in order to allow for the uptake of the drug by the respective tissues. A problem of this route of administration is that the normal amount of liquid (tear fluid) present in this region is about 7 μl, most of which resides in the conjunctival sac, while some covers the cornea. The addition of fluid is possible, but probably the holding capacity of the front of an eye is limited to about 30 μl (NM Davies, ibid.). Considering the fact that aqueous eye drops usually have a volume in the region of 50 μl per drop, this illustrates that large fractions of administered drug will normally be lost immediately upon administration through spillage or overflow. Subsequently, drug will be eliminated from the site of administration via the continuous physiological turnover of tear fluid, which occurs at a rate of approx. 1 μl—or about 16%—per minute. These two rapid clearance mechanisms can make the effective local delivery of those drugs rather challenging which are taken up only slowly.
If the target site is the cornea itself, or the anterior or posterior chamber, intraocular absorption from the site of administration at the front of the eye is required. It is believed that the major route of absorption into the eye is through the cornea (I Ahmed, Int. J. Pharm. 38, 9-21, 1987). As the cornea is rather small in its surface area and poorly permeable in comparison with the vascularised conjunctiva, the absorption into the eye is generally not very efficient and leads to intraocular bioavailabilities in the range of only 1-10%. The poor permeability results from the structure of the cornea, which in essence comprises three layers: the outer epithelium, the stroma, and the inner endothelium. Due to the hydrophilic nature of the stroma and the lipophilic epithelial layers, the cornea presents an effective diffusion barrier to both lipophilic and hydrophilic compounds.
Nevertheless, topical ophthalmic delivery, while not highly efficient in absolute terms, is still relatively effective for many small molecular drugs, and acceptable to patients in terms of convenience. As mentioned, most ophthalmic drug products are presented as eye drops or ointments for topical administration. While most of the eye drop formulations are aqueous solutions, the properties of certain drug substances, in particular in terms of solubility and/or hydrolytic instability, present substantial challenges for this type of formulation, so that ophthalmic suspensions remain to be an important alternative to solutions, in spite of their problems as discussed above.
As an alternative to aqueous preparations, oily eye drops may be formulated if the respective drug substance is poorly water-soluble or prone to hydrolytic degradation. However, one of the major disadvantages of all oil-based formulations for ophthalmic administration is that they inherently have a negative impact on vision. Whether used as oily solutions or oil-in-water emulsions, they exhibit a refractive index which differs substantially from that of physiological tear fluid, which leads to visual disturbances and blurring.
Moreover, oil-based formulations do not readily mix with tear fluid to form a homogenous liquid phase. Oily solutions are altogether immiscible with the aqueous tear fluid, and the exact fate of an emulsion mixed with tear fluid in a physiological setting is not completely predictable.
Oil-in-water emulsions of poorly water-soluble drugs like ciclosporin further exhibit the disadvantage that they have a limited drug load capacity. While the active ingredient may have some solubility in the oil phase, this phase is only dispersed in the coherent aqueous phase of the emulsion so that the maximum overall drug concentration in the formulation is very limited.
In contrast to single phase systems such as aqueous or oily solutions, oil-in-water emulsions are also more complex and difficult to manufacture, especially in sterile form. Frequently, emulsions are not readily sterilisable by thermal treatment without negative impact on the physical properties of the emulsion. On the other hand, aseptic processing is complex, costly, and is associated with higher risks of failure, i.e. microbial contamination of the product.
Furthermore, oil-in-water emulsions are like aqueous solutions prone to microbial contamination during use. If they were to be presented in multi-dose containers which are in principle more cost-efficient and convenient for patients than single-use vials, they would have to be preserved in order to ensure their microbiological quality. At the same time, preservatives which can be used in ophthalmic formulations are potentially damaging to the eye, in particular to the ocular surface, and should be avoided whenever possible.
As another alternative to aqueous liquid carriers which are problematic for water-sensitive drug substances, U.S. Pat. No. 6,458,376 proposes eye drops on the basis of non-aqueous liquid perfluorocarbons. At least some of the preferred perfluorocarbons are presented as biocompatible and non-irritating to the eye. The compositions are formulated as suspensions, in particular of polymeric carrier particles which include the drug substance and which are capable of releasing the drug slowly over an extended period of time. Moreover, the compositions may comprise a surfactant such as a non-ionic ethoxylated alcohol or sorbitan. The surfactant functions as a suspension stabiliser and prevents aggregation.
However, it has been found by the present inventors that these drug suspensions in perfluorocarbons suffer from various disadvantages. If formulated without surfactant, they tend to separate (by flotation, or sometimes by sedimentation) very rapidly, and lead to substantial particle aggregation. At the same time, the settled suspensions are very difficult to redisperse by shaking alone. These poor physical suspension properties would seriously impact their usefulness as eye drops. Not only is vigorous shaking and the need for rapid administration before the suspension separates again very inconvenient to patients; poor suspension properties are also associated with the risk of substantial dosing errors. On the other hand, surfactants, which are potentially irritating to the eye and whose use in ophthalmic preparations should be avoided or limited to a low level, are not very effective in stabilising perfluorocarbon suspensions. The incorporation of high amounts of surfactant which may achieve a better stabilisation of the suspension system is physiologically undesirable.
In the context of aerosol delivery of lung surfactant, WO 2005/099718 mentions that semifluorinated alkanes such as perfluorooctylethane or perfluorohexyldecane may be used as liquid carriers of surfactant substitutes, for example native or synthetic phospholipids. The document is silent about the delivery of poorly soluble or chemically instable drug substances, let alone for the purpose of topical administration to the nose or eye, or by injection. Neither does it disclose any other systems beyond colloidal solutions of surfactants.
There is a need for further improvements in the formulation of poorly-soluble or water-sensitive drugs. In particular, there is a need for liquid drug formulations which are suitable for the ophthalmic, injectable, and/or other routes of administration and which do not possess one or more of the disadvantages of prior art compositions. There is also a need for improved suspension formulations which are physically stable and easy to handle, as well as improved non-aqueous formulations for hydrolytically sensitive drug substances.
It is therefore an object of the present invention to provide a novel pharmaceutical composition which is useful for the delivery of poorly-soluble and/or water-sensitive drug substances. Another object is to provide improved formulations for topical ophthalmic delivery which overcome one or more disadvantages of known formulations. It is also an object to provide further improved composition which may be delivered via the injectable route. Moreover, it is an object to provide pharmaceutical suspensions with improved suspension properties. A further object is to provide improved non-aqueous liquid formulations which overcome the limitations of presently known formulations. Further objects of the invention will become clear on the basis of the following description, examples, and patent claims.